By December 2019, the simple diamond interchange with 59th Avenue (exit 138) was totally rebuilt, transforming it into the first of two junctions with the Loop 202 Ed Pastor Freeway.

Near 3rd Avenue, the highway enters a half-mile tunnel (800 m) that runs under a park and the central branch of the City of Phoenix Library.

Emerging past 3rd Street, the highway continues due eastward for another two miles (3.2 km) before coming to another interchange for Route 51 and Loop 202 (second of three junctions with the latter), called the Mini Stack.

Past Loop 202, the highway turns to a more south by southeast direction going through the Gila River Indian Community and entering Pinal County.

[5] After exiting the Phoenix metropolitan area, I‑10 continues southward into Casa Grande intersecting I‑8 before heading southeast towards Tucson, paralleling the Santa Cruz River.

Particularly east of Eloy, it follows the Butterfield Stage and Pony Express routes, and loops south to avoid the north–south Basin and Range mountains prevalent in the state.

The two old federal routes then struck west across the desert and state line, picking up the Southern Pacific mainline at Indio, California, and I-10 overlies the old roads most of that distance.

In 1960, this westernmost stretch of I-10 was built from near the Colorado River east to the future spot where the "Brenda Cutoff" section of I-10 would connect a decade later.

Now an obscure name, "Brenda Cutoff" was the working title that the Arizona Highway Department called the stretch of freeway from US 60 to near Buckeye.

The Brenda Cutoff paralleled old sand roads used in the 1920s for Phoenix-Los Angeles traffic, but mostly abandoned after US 60/US 70 was built to the north, through Wickenburg.

The Brenda Cutoff's opening on June 18, 1973 was eagerly awaited and was a big deal in newspapers in Phoenix and Los Angeles.

In addition, there was only one very-small gas station on the very-long route between Buckeye and Quartzsite, on the old county road at the tiny crossroads of Palo Verde.

Voters on election day were treated to a photo depiction on the front page of the newspaper that in later years was shown to have drastically overstated the freeway's height, but there is no question the proposed viaducts and helicoils would have been a visual gash across central Phoenix.

Beginning in 1961, a stub of what is now the Inner Loop portion of I‑10 was built northward from the Maricopa Freeway (then I‑10) along 20th Street, ending 0.5 miles (0.80 km) north at Buckeye Road.

Despite some local opposition, I-10 was finally completed in central Phoenix on the Inner Loop alignment, 0.75 miles (1.21 km) north of Van Buren Street, on August 10, 1990.

[9] The state is now considering a reliever freeway in West Phoenix, parallel to I-10 on the old Durango Street corridor, and was originally designated as Route 801, which has since been changed to SR 30.

The I-10 signs were moved from the Maricopa Freeway to the Papago Freeway/Inner Loop alignments when it opened in 1990—the last gap of I-10 to be completed between Santa Monica and Jacksonville.

The freeway through Tucson, which was rebuilt and widened in stages from 1989 to 2014, with frontage roads added, was originally signed as SR 84 from Miracle Mile to Sixth Avenue.

The original highway from Casa Grande to Tucson entered the Old Pueblo via Miracle Mile, a road modeled after German Autobahns but without overpasses or an exclusive right of way.

The present-day I‑10 alignment along the Santa Cruz River was laid out after a city bond issue passed in 1948 to build a riverbank-side boulevard with room for a four-lane freeway in the median to follow.

[16] In 1958, the state added the bypass to the Interstate Highway System as part of I-10 and began converting it to full freeway standards.

The last section of old US 80 that carried the I‑10 traffic was an underpass beneath the Union Pacific mainline east of Tucson, where the freeway median shrank to a guardrail at Marsh Station Road and the Pantano railroad overpass was too low.

[19][20] From Benson, the interstate follows the Southern Pacific mainline east through Willcox and Bowie to New Mexico, rather than bend south to the Mexican border along old US 80 (signed as SR 80 after 1989), through Douglas.

The road from Benson east through Willcox was designated SR 86 in about 1935, that route number was subsequently shifted west and exists now between Why and Tucson.

The $1 billion project also received a $95 million federal grant in January 2024; the state and the Maricopa Association of Governments will provide the rest of the funding.

In December 2020, ADOT released final design concept report that will widen I-10 by two to four lanes from the I-19 to Kolb Road interchanges.